CN104721183B - A kind of drug combination preparation containing Piracetam and preparation method thereof - Google Patents
A kind of drug combination preparation containing Piracetam and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to field of medicine preparations, it is related to a kind of drug combination preparation containing Piracetam and preparation method thereof, and in particular to a kind of medicine composition injection containing Piracetam and ethacrynate sodium and preparation method thereof.Parenteral solution of the present invention contains the Piracetam and ethacrynate sodium of effective dose, can act synergistically on encephaledema, strengthens the effect of antioedematous, preferably reduces brain water content, rise MOD and reduction MDA.
Description
Technical field
The invention belongs to field of medicaments, it is related to a kind of drug combination preparation containing Piracetam and preparation method thereof,
Specifically related to a kind of medicine composition injection containing Piracetam and ethacrynate sodium and preparation method thereof.
Background technology
Encephaledema refers to the increase of intracerebral moisture, the pathological phenomenon for causing brain volume to increase, be brain tissue to it is various it is pathogenic because
The reaction of element.Intracranial hypertension can be caused, injured brain tissue is clinically common in the nervous system disease, such as craniocerebral trauma, intracranial infection
(encephalitis, meningitis etc.), cranial vascular disease, Intracranial mass lesion (such as tumour), epileptic attack and systemic disease are as in
Toxicity dysentery, severe pneumonia.The pathogenesis of encephaledema is extremely complex, and correlative factor is a lot, blood-brain barrier, microcirculation disorder,
Cerebral ischemia and anoxic, the increase of intracerebral free radical, the change of thromboxane A2 and prostacyclin, the change of neurotransmitter and neuropeptide
Change.Nerve cell calcium overload etc. can influence the generation and development of encephaledema.Encephaledema makes hydrocephalus, and hydrocephalus can aggravate brain again
Oedema, is developed to a certain degree, you can make brain tissue generating function and the infringement in structure.If can not diagnose and locate in time
Reason, encephaledema is aggravated, or develops into diffusivity by limitation, and serious harm will be produced to brain, forms the Secondary cases of irreversibility
Pathological change, occurs brain death.This final result, is that brain tissue generality is undermined and the secondary brain stem of hernia cerebri seriously damages caused.
Piracetam (oxiracetam) was synthesized by Italian SmithKline than Qie Mu company (ISF) in 1974, and chemistry is entitled
Esomeprazole, the racemic modification being made up of (R)-Piracetam and (S)-Piracetam should
Medicine is the beta-hydroxy derivative of Piracetam, is a kind of hydroxy-amino-butyric acid (GABOB) cyclic derivatives.Piracetam is one
Nootropics is planted, senile dementia and memory and the learning functionality of memory disorder patient can be improved.Result of study shows that pyrrole is drawn
The western smooth ratio for promoting Phosphorylcholine and phosphatidyl ethanolamine to synthesize, improving ATP/ADP in brain, makes protein and core in brain
The synthesis increase of acid, clinically for brain damage and caused neurological deficit, memory and the treatment of disturbance of intelligence.
Piracetam structural formula is as follows：
Ethacrynic acid also known as ethacrynic acid, diuresis are powerful, rapid, reliable, it is adaptable to oedema caused by the various causes of disease, face
Bed is used for congestive heart failure, acute pulmonary edema, renal edema, cirrhotic ascites, ascites of liver cancer, snail fever ascites, brain
Oedema and other oedema.But ethacrynic acid has very big adverse reaction, common person is relevant with water and rock-soil coupling, especially big
When dosage or prolonged application, such as postural hypotension, shock, hypopotassaemia, hypochloraemia, hypochloremic alkalosis, hyponatremia,
Hypocalcemia and relevant with this thirsty, weak, DOMS, arrhythmia cordis etc..Rare person has allergic reaction (including skin
Rash, even interstitial nephritis, heart arrest), the dimness of vision, xanthopsy, photaesthesia, dizziness, have a headache, receive poor, Nausea and vomiting,
Stomachache, diarrhoea, pancreatitis, muscle rigidity etc., bone marrow suppression causes granulocyte to reduce, thrombocytopenic purpura and aregeneratory
Property anaemia, hepatic disorder refers to, toe cacesthesia, and hyperglycemia, glucose in urine is positive, and original diabetes are aggravated, hyperuricemia.
But gastrointestinal reaction, watery diarrhea and ototoxicity are common compared with FRUSEMIDE.Still cause blood urine and hemorrhage of digestive tract.There is stronger ear
Source property toxicity, it is clinically less at present to use.
Because ethacrynic acid is water insoluble, clinical injection needs to use its sodium salt, and needs before use with 5% glucose injection
Slow after liquid or physiological saline 50ml dilutions to instil or intravenous, match somebody with somebody solution must use complete in 24 hours, to medical worker with
Carry out operational trouble and occur the possibility of mistake, and be easier to cause secondary pollution in operation.
Ethacrynate sodium, is [2,3- bis- chloro- 4- (2- methylene bytyry) phenoxy group] sodium acetate.Structural formula is as follows：
The content of the invention
Based on the above-mentioned problems in the prior art, inventor determines the pharmaceutical composition system of exploitation treatment encephaledema
Agent.It is an object of the invention to provide a kind of parenteral solution containing Piracetam and ethacrynate sodium.The parenteral solution contains effectively
The Piracetam and ethacrynate sodium of amount, can act synergistically on encephaledema, strengthen the effect of antioedematous, preferably reduce brain tissue
Water content, rise MOD and reduction MDA.
In order to realize foregoing invention purpose, inventor adopts the following technical scheme that：
The medicine composition injection that the present invention is provided, is Piracetam, the ethacrynate sodium of effective dose by effective dose
It is prepared from pharmaceutically acceptable auxiliary material or complementary composition.Because Piracetam is easily hydrolyzed, product quality is caused to reduce；
And complementary composition such as buffer used can effectively suppress the hydrolysis of product in the present invention, the stability of product is significantly improved.
Specifically, in medicine composition injection of the present invention, per 1000ml parenteral solutions in containing Piracetam 30-50g, according to
The sour sodium 0.25-1g of his Buddhist nun.
Also comprised the following components in the every 1000ml of present composition parenteral solution：Isotonic regulator 40-60g, buffer
0.1-5g。
Contain Piracetam 35-45g, ethacrynate sodium 0.4-0.7g in every 1000ml parenteral solutions in parenteral solution of the present invention,
Isotonic regulator 45-55g, buffer 0.5-1.5g.
Preferably, per 1000ml parenteral solutions in contain Piracetam 40g, ethacrynate sodium 0.5g, isotonic regulator 50g,
Buffer 1g.
The isotonic regulator of parenteral solution of the present invention is the one or more in glucose, xylitol；Buffer is selected from phosphoric acid
One or more in sodium dihydrogen, citric acid, tartaric acid, glycine, malic acid, arginine and fumaric acid.
The pH value of parenteral solution of the present invention is 5.5~6.5.
The preparation technology of parenteral solution of the present invention is as follows：
(1) isotonic regulator, buffer are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value to 5.5
~6.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
The present invention is also claimed aforementioned pharmaceutical compositions and is preparing the purposes in treating or preventing encephaledema medicine.This hair
Bright test example 1 have studied pharmaceutical composition of the present invention and protection of the bilateral common carotid arteries with models of hypotention cerebral ischemia ligatured to rat
Effect, result of study shows that two kinds of medicines of Piracetam and ethacrynate sodium ligature bilateral common carotid arteries with low in reduction rat
There is significant synergy in terms of blood pressure model brain water content, reduction MDA contents and increased SOD content, brain can be mitigated
Damage of the oedema to cerebral tissue, and its effect is significantly better than existing Piracetam and frusemide drug regimen.
Compared with prior art, the invention has the advantages that：
1) pharmaceutical composition of the invention is using Piracetam and ethacrynate sodium as main active, its for brain outside
Wound, cerebral hemorrhage, cerebral infarction, meningitis, brain tumor etc. be sick and wounded and cerebral surgery operation caused by encephaledema be respectively provided with good control
Therapeutic effect.Specifically, test example 1 of the present invention have studied pharmaceutical composition of the present invention and bilateral common carotid arteries ligatured to rat with low blood
The protective effect of pressing mold type cerebral ischemia, result of study shows that pharmaceutical composition of the present invention has notable in terms of encephaledema is treated
Synergy, and can reduce the MDA contents in cerebral tissue and increased SOD content, reduce encephaledema to cerebral tissue
Infringement, be more beneficial for the protection of cerebral tissue after encephaledema.
2) two kinds of Drug combinations can reduce by two kinds of medicines while drug effect is improved in pharmaceutical composition of the present invention
Exclusive use amount, its drug side-effect is lower, thus with higher compliance, consolidated the therapeutic effect of medicine.
3) present invention creatively adds isotonic regulator, avoids the trouble prepared during clinical practice and occurs mistake
Possibility, it is to avoid secondary pollution of the medicine in process for preparation.
4) present invention achieves unexpected technique effect, its reasonable recipe, and technique is simple, and stability is good.Specifically,
Through the factors influencing 10 days under the conditions of high temperature, high humidity and strong illumination and 40 DEG C of accelerated tests 6 months, sample appearance
Shape, pH, active constituent content and relevant material etc. are had no significant change, and compared with reference examples, stability is dramatically increased.
Embodiment
The present invention is further illustrated by the following examples, but these embodiments do not limit the present invention in any way.
Embodiment 1：
Prescription：
Preparation technology：
(1) glucose, citric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.0, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 2：
Prescription：
Preparation technology：
(1) glucose, malic acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.0, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 3：
Prescription：
Preparation technology：
(1) glucose, glycine are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.0, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 4：
Prescription：
Preparation technology：
(1) glucose, citric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
5.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 5：
Prescription：
Preparation technology：
(1) glucose, sodium dihydrogen phosphate are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
5.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 6：
Prescription：
Preparation technology：
(1) glucose, sodium dihydrogen phosphate are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
5.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 7：
Prescription：
Preparation technology：
(1) glucose, tartaric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 8：
Prescription：
Preparation technology：
(1) glucose, fumaric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Embodiment 9：
Prescription：
Preparation technology：
(1) glucose, arginine are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of addition recipe quantity, ethacrynate sodium are stirring while adding to complete molten to wherein, adjust pH value extremely
6.5, add to the full amount of water for injection.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Reference examples 1：
Prescription：
Preparation technology：
(1) glucose, citric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of recipe quantity is added to wherein, it is stirring while adding to complete molten, pH value is adjusted to 6.0, plus water for injection
To full dose.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Reference examples 2：
Prescription：
Preparation technology：
(1) glucose, tartaric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of recipe quantity is added to wherein, it is stirring while adding to complete molten, pH value is adjusted to 6.0, plus water for injection
To full dose.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Reference examples 3：
Prescription：
Preparation technology：
(1) glucose, citric acid are added in the water for injection for preparing total amount 30%, stirred to complete molten.
(2) Piracetam of recipe quantity is added to wherein, it is stirring while adding to complete molten, pH value is adjusted to 6.0, plus water for injection
To full dose.
(3) 0.01~0.05% (w/v) activated carbon is added, insulated and stirred 20 minutes filters carbon removal.
(4) 0.22um miillpore filter refined filtrations are used.
(5) embedding is in glass ampule, sealing.
(6) 121 DEG C, pressure sterilizing 15 minutes.
(7) lamp inspection, packaging.
Test example：Technical scheme is further described below by test example：
Test example 1, pharmaceutical composition of the present invention ligature guarantor of the bilateral common carotid arteries with models of hypotention cerebral ischemia to rat
Shield is acted on
1 materials and methods
1.1 medicines and reagent
Nimodipine tablet：It is commercially available.
With normal saline, into required concentration is used in experiment for by reagent and positive control drug.
MDA (MDA), superoxide dismutase (SOD) and Ca2+ kits are purchased from Nanjing and build up biotechnology research
Institute.
1.2 experimental animal SD rats, male, 250~300g of body weight has purchased from Suzhou City industrial park Ai Ermaite science and technology
Limit company, credit number：SCXK (Soviet Union) 2009-0001.
The multichannel arteria caudalis pressure measurement experimental systems (Shanghai) of 1.3 instrument and equipment BESN- II, table-type high-speed refrigerated centrifuge
(sigma, the U.S.).
1.4 animal packets and administration take SD male rats, and 8 groups are randomly divided into by body weight, every group 10, i.e.,：Sham-operation group,
Model group, Nimodipine (positive drug) group, Piracetam frusemide (pyrrole+furan) group, Piracetam list medicine group, ethacrynate sodium
Low group of (according to him), high group of ethacrynate sodium (according to him) and the high, medium and low dosage group of pharmaceutical composition of the present invention.
(as shown in table 1, sham-operation group and model group give isometric life to dosage to the equal intraperitoneal injection of each group animal
Manage salt solution), one time a day, continuous 7d.In the detection that indices are carried out after last dose 24h.
Foundation of the 1.5 rats ligation bilateral common carotid arteries with models of hypotention
Animal is in the chloraldurate 0.3mL/kg intraperitoneal anesthesias of 1h after last dose, rat-tail measuring blood pressure, and plastic tube is outside neck
Vein inserts atrium dextrum for bloodletting.With the method bloodletting of blood drawing, losing blood, it is double blood pressure is separated when reaching 10.7kPa (80mmHg)
Side arteria carotis communis is simultaneously ligatured, and is further continued for blood drawing, as drop in blood pressure to 6.7kPa (50mmHg), now causes imperfection brain
Ischemia model, maintains 15min.Sham-operation group is only intubated, not bloodletting and ligation.The blood of extraction is put into heparinised tubes, 37 DEG C
Water-bath is preserved, in case being fed back during hypopiesia.After 15min, sacrificed by decapitation opens cranium and takes brain, taken after removing rhinencephalon, brain stem, cerebellum
Hemisphere on the left of brain, right side is placed on ice basin, washes away residual blood with ice physiological saline, quality and volume ratio by 1: 9 under ice bath with
Ice physiological saline for homogenate medium prepare 10% brain tissue homogenate, packing into 4 1.5mLEp-pendorf pipes in 4 DEG C, with
3500r/min centrifuges 10min, takes supernatant to determine brain tissue MDA, SOD level respectively using ELIASA.At the same time, left brain
Claim brain wet weight, be then placed in 110 DEG C of baking boxs and bake to constant weight, claim its dry weight, calculate brain water content.1 animal of every group of taking-up, breaks
Head is put to death, and is opened cranium and is taken brain, takes brain to wash down after residual blood after removing rhinencephalon, brain stem, cerebellum, is put into 10% formaldehyde fixed, routine
FFPE, HE dyeing, light Microscopic observation pathological change.
Brain water content=(brain wet weight-brain stem weight)/brain wet weight × 100%
All data of 1.6 statistical procedures are represented with mean ± standard deviation, and progress statistical is examined using t is compared between group
Analysis.
(1) pharmaceutical composition of the present invention ligatures shadow of the bilateral common carotid arteries with models of hypotention brain water content to rat
Ring (experimental result is shown in Table 1).
The pharmaceutical composition of the present invention of table 1 ligatures shadow of the bilateral common carotid arteries with models of hypotention brain water content to rat
Ring
| Group | Dosage | Brain water content |
| Sham-operation group | Isometric physiological saline | 26.12±0.75 |
| Model group | Isometric physiological saline | 39.43±1.14 |
| Positive controls | 200mg/kg/d Nimodipines | 36.22±0.87* |
| Pyrrole+furan group | 200mg/kg Piracetam+2mg/kg frusemides | 34.14±0.78 |
| Piracetam group | 200mg/kg/d Piracetams | 35.33±1.09 |
| According to he low group | 1mg/kg/d ethacrynate sodiums | 34.59±0.68*#▲ |
| Yi Tagao groups | 2mg/kg/d ethacrynate sodiums | 33.73±0.86**#▲ |
| Composition A groups | 1mg/kg/d ethacrynate sodium+100mg/kg/d Piracetams | 28.82±0.56**#▲▲◆★△ |
| Composition B groups | 1mg/kg/d ethacrynate sodium+200mg/kg/d Piracetams | 27.98±0.72**##▲▲◆★△△ |
| Composition C groups | 2mg/kg/d ethacrynate sodium+200mg/kg/d Piracetams | 27.21±0.52**##▲▲◆★△△ |
Compared with model group,*P ＜ 0.05,**P ＜ 0.01；
Compared with positive controls,#P ＜ 0.05；##P ＜ 0.01；
Compared with Piracetam group,▲P ＜ 0.05,▲▲P ＜ 0.01；
Compared with low group of ethacrynate sodium,◆P ＜ 0.05；
Compared with high group of ethacrynate sodium,★P ＜ 0.05；
Compared with pyrrole+furan group,△P ＜ 0.05,△△P ＜ 0.01.
As can be seen from Table 1, model group is compared with sham-operation group, and brain water content has pole significant difference, modeling success.
Positive controls, pyrrole+furan group, Piracetam list medicine group, ethacrynate sodium high and low dose group are respectively provided with certain encephaledema and made
With wherein pharmaceutical composition of the present invention can significantly or pole significantly decreases rat ligation bilateral common carotid arteries with models of hypotention brain
Tissue water content, mitigates encephaledema.Two kinds of medicines of Piracetam and ethacrynate sodium are in reduction rat ligation bilateral common carotid arteries
There is significant synergy in terms of with models of hypotention brain water content, and its effect is significantly better than existing Piracetam
With frusemide drug regimen.
(2) pharmaceutical composition of the present invention ligatures the influence of bilateral common carotid arteries companion's models of hypotention SOD, MDA to rat (in fact
Test and the results are shown in Table 2).
The pharmaceutical composition of the present invention of table 2 is to influence of the ligation bilateral common carotid arteries with models of hypotention rat SOD, MDA
| Group | SOD(U.mg-1) | MDA(nmol.mg-1) |
| Sham-operation group | 9.78±0.86 | 3.89±0.52 |
| Model group | 4.87±0.73 | 6.09±0.65 |
| Positive controls | 6.12±0.83* | 5.34±0.49* |
| Pyrrole+furan group | 7.23±0.56 | 4.95±0.64 |
| Piracetam group | 5.26±0.87 | 5.91±0.53 |
| Low group of ethacrynate sodium | 6.53±0.67*▲▲ | 5.42±0.59*▲ |
| High group of ethacrynate sodium | 6.89±0.56*#▲▲ | 5.23±0.42*#▲▲ |
| Composition A groups | 8.11±0.48**#▲▲◆★△ | 4.82±0.57**#▲▲◆★△ |
| Composition B groups | 8.83±0.74**##▲▲◆★△△ | 4.32±0.43**##▲▲◆★△△ |
| Composition C groups | 9.45±0.59**##▲▲◆★△△ | 3.98±0.68**##▲▲◆★△△ |
Compared with model group,*P ＜ 0.05,**P ＜ 0.01；
Compared with positive controls,#P ＜ 0.05；##P ＜ 0.01；
Compared with Piracetam group,▲P ＜ 0.05,▲▲P ＜ 0.01；
Compared with low group of ethacrynate sodium,◆P ＜ 0.05；
Compared with high group of ethacrynate sodium,★P ＜ 0.05；
Compared with pyrrole+furan group,△P ＜ 0.05,△△P ＜ 0.01.
As can be seen from Table 2, model group is compared with sham-operation group, SOD and MDA contents have pole significant difference, modeling
Success.Positive controls, pyrrole+furan group, Piracetam list medicine group, ethacrynate sodium height group, it is respectively provided with certain rise brain group
The effect of middle SOD contents and reduction MDA contents is knitted, wherein pharmaceutical composition of the present invention can significantly or pole significantly changes rat knot
Bilateral common carotid arteries are pricked with models of hypotention SOD contents and MDA contents, mitigate damage of the encephaledema to cerebral tissue.Pyrrole draws west
Smooth and two kinds of medicines of ethacrynate sodium are in reduction rat ligation bilateral common carotid arteries with models of hypotention MDA contents and increased SOD
There is significant synergy in terms of content, and its effect is significantly better than existing Piracetam and frusemide drug regimen.
The development test of test example 2, parenteral solution of the present invention
(1) screening of buffer and pH value：
(1) buffer is screened
Prescription according to table 3 prepares sample, under the conditions of the sample of preparation is placed into 60 DEG C after 10 days, investigates the pH of parenteral solution
Value, content and the change about material, the results are shown in Table 4.
Table 3：Prescription and each component consumption
Under the conditions of 4 60 DEG C of table after 10 days, the content of each prescription and the situation of change about material
Note：This test buffer agent is citric acid.Other bufferses for example sodium dihydrogen phosphate, tartaric acid, glycine, malic acid,
Arginine, fumaric acid result of the test are similar, unlisted.
Result of the test shows：Buffer is added in prescription can significantly improve product quality.
(2) determination of pH value range
According to the prescription and pH value of table 5, under the conditions of the sample of preparation is placed into 60 DEG C after 10 days, the pH of parenteral solution is investigated
Value, content and the change about material, the results are shown in Table 6.
The composition and pH value of the parenteral solution of table 5
Under the conditions of 6 60 DEG C of table after 10 days, pH value, content and the situation of change about material of each prescription
Result of the test shows that parenteral solution of the present invention is stable in the range of pH value is 5.5~6.5.Therefore, in the present invention
In, the pH value range of parenteral solution of the present invention is 5.5~6.5.
(2) further, inventor is investigated to the stability of prescription, as follows：
Influence factor is tested
Extract injection liquid samples (removal outer packing) prepared by embodiment 1 carries out respectively (60 DEG C ± 2 DEG C) of high temperature influence because
Element experiment 10 days and high temperature illumination (4500Lx ± 500Lx) influence factor are tested 10 days.In the 5th day, sampling detection in the 10th day was high
What temperature was tested the results are shown in Table 7, exposure experiments to light result table 8.
The hot test result of table 7
As a result show：
Sample prepared by embodiment 1 is placed after 10 days appearance luster, clarity, pH value, content and had under the high temperature conditions
Close material and be showed no significant change.
The exposure experiments to light result of table 8
As a result show：
Sample prepared by embodiment 1 is placed under hot conditions (60 DEG C ± 2 DEG C) and illumination condition (4500Lx ± 500Lx)
After 10 days, appearance luster, visible foreign matters, pH value, content and relevant material are showed no significant change.
Accelerated test
Extract embodiment 1, the packaging sample of reference examples 1 and be positioned over 40 DEG C ± 2 DEG C, the climatic chamber of RH75% ± 5%
Interior storage six months, in the 1st, 2,3,6 the end of month, respectively sampling once checks that result of the test is shown in Table 9.
The accelerated test result of table 9
As a result show：
The packaging sample of embodiment 1 appearance luster, clarity, pH value, content and has after the accelerated test of 6 months
Close material and be showed no significant change；Compared with the packaging sample of reference examples, stability is more preferable.
Long term test
Extract embodiment 1, the packaging sample of reference examples 1 and be placed in room temperature placement, it is each in the 3rd, 6,9,12,18,24 the end of month
Sampling once checks that result of the test is shown in Table 10.
The long-term test results of table 10
As a result show：
The packaging sample of embodiment 1 after the long term test of 24 months, appearance luster, visible foreign matters, pH value, content and
Relevant material is showed no significant change；Compared with the packaging sample of reference examples, stability is more preferable.
Conclusion (of pressure testing)
The experiment of above influence factor, accelerated test and long-term test results show that injection products prepared by the present invention have
There is good stability, can ensure that the security, validity and stability of medicine.
Claims (4)
1. a kind of medicine composition injection for treating encephaledema, it is characterised in that draw west containing pyrrole in per 1000ml parenteral solutions
Smooth 40g, ethacrynate sodium 0.5g, isotonic regulator glucose 50g, buffer 1g, the pH value of the parenteral solution is 5.5~6.5.
2. parenteral solution as claimed in claim 1, it is characterised in that described buffer is selected from sodium dihydrogen phosphate, citric acid, wine
One or more in stone acid, glycine, malic acid, arginine and fumaric acid.
3. the preparation technology of parenteral solution as claimed in claim 1, it is characterised in that comprise the following steps：
（1）Isotonic regulator, buffer are added in the water for injection for preparing total amount 30%, stirred to complete molten；
（2）The Piracetam of recipe quantity, ethacrynate sodium are added to wherein, it is stirring while adding to complete molten, tune pH value to 5.5~
6.5, add to the full amount of water for injection；
（3）0.01~0.05%w/v activated carbons are added, insulated and stirred 20 minutes filters carbon removal；
（4）With 0.22um miillpore filter refined filtrations；
（5）Embedding is in glass ampule, sealing；
（6）121 DEG C, pressure sterilizing 15 minutes；
（7）Lamp inspection, packaging.
4. the parenteral solution described in claim 1 or 3 is preparing the purposes in treating or preventing encephaledema medicine.
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| CN201510165373.9A CN104721183B (en) | 2015-04-09 | 2015-04-09 | A kind of drug combination preparation containing Piracetam and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1250651A (en) * | 1998-10-09 | 2000-04-19 | 和光学 | Medicinal composition for preventing and curing intracranial hypertension |
| CN102964225A (en) * | 2012-12-18 | 2013-03-13 | 浙江大洋生物科技集团股份有限公司 | Preparation method of 2, 3-dichloroanisole |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101172105A (en) * | 2007-11-27 | 2008-05-07 | 北京润德康医药技术有限公司 | Use of levetiracetam in preparing intelligence benefiting medicament |
| CN101375847A (en) * | 2008-08-12 | 2009-03-04 | 珠海和凡医药有限公司 | Medicament composition with dehydration and diuresis functions |
| CN102008430A (en) * | 2010-12-17 | 2011-04-13 | 张家港市华菱化工机械有限公司 | Piracetam-containing oral liquid |
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2015
- 2015-04-09 CN CN201510165373.9A patent/CN104721183B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1250651A (en) * | 1998-10-09 | 2000-04-19 | 和光学 | Medicinal composition for preventing and curing intracranial hypertension |
| CN102964225A (en) * | 2012-12-18 | 2013-03-13 | 浙江大洋生物科技集团股份有限公司 | Preparation method of 2, 3-dichloroanisole |
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